{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:49:39Z","timestamp":1791478179560,"version":"4.3.4"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Cell Biology","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R35GM144082"],"award-info":[{"award-number":["R35GM144082"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Variants at the CD2AP locus, which encodes a branched-actin regulator, are associated with late-onset Alzheimer\u2019s disease (AD), and CD2AP-deficient mice show increased blood-brain barrier (BBB) permeability. CD2AP is enriched in endothelial cells, but its function there is poorly understood. In endothelium, branched actin networks maintain cell-cell junctions and are also required for immune cells to cross through individual endothelial cells (transcellular transendothelial migration, TEM). We previously showed that the Arp2\/3 activators N-WASP and WAVE2 contribute to these processes, but the capping protein (CP)-interacting proteins involved are unknown. Here we tested whether CD2AP, a CP-interacting protein recruited to cell-cell contacts, regulates both junction integrity and TEM. In primary human microvascular endothelial cells, shRNA knockdown of CD2AP increased TNF\u03b1-induced monolayer permeability, measured by transendothelial electrical resistance, and altered VE-cadherin junction morphology. Unexpectedly, on soft hydrogels the same knockdown reduced TEM of NK-92 MI cells, lowering the proportion of transcellular events. Thus, loss of CD2AP weakens the endothelial barrier yet impairs a distinct, actin-dependent route of immune-cell passage. These findings suggest that CD2AP risk variants may affect the BBB through more than permeability, and they identify endothelial immune-cell trafficking as a testable link between CD2AP and AD.<\/jats:p>","DOI":"10.64898\/2026.10.01.755982","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:45:15Z","timestamp":1790970315000},"source":"Crossref","is-referenced-by-count":0,"title":["The Alzheimer\u2019s Disease-associated gene CD2AP regulates permeability of endothelial cells and transendothelial migration of immune cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-1105","authenticated-orcid":false,"given":"Michael D","family":"Onken","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0933-4571","authenticated-orcid":false,"given":"John A","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100808500718000_2026.10.01.755982v2.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600166200"},{"key":"2026100808500718000_2026.10.01.755982v2.2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv371"},{"key":"2026100808500718000_2026.10.01.755982v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.056"},{"key":"2026100808500718000_2026.10.01.755982v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9415"},{"key":"2026100808500718000_2026.10.01.755982v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.111013"},{"key":"2026100808500718000_2026.10.01.755982v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng.803"},{"key":"2026100808500718000_2026.10.01.755982v2.7","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.109447"},{"key":"2026100808500718000_2026.10.01.755982v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00124-7"},{"key":"2026100808500718000_2026.10.01.755982v2.9","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E18-02-0136"},{"key":"2026100808500718000_2026.10.01.755982v2.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-0436.2007.00255.x"},{"key":"2026100808500718000_2026.10.01.755982v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/nature05453"},{"key":"2026100808500718000_2026.10.01.755982v2.12","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2000.279.4.F785"},{"key":"2026100808500718000_2026.10.01.755982v2.13","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-015-0006-y"},{"key":"2026100808500718000_2026.10.01.755982v2.14","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-05-0976"},{"key":"2026100808500718000_2026.10.01.755982v2.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.668285"},{"key":"2026100808500718000_2026.10.01.755982v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/ng.801"},{"key":"2026100808500718000_2026.10.01.755982v2.17","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21203"},{"key":"2026100808500718000_2026.10.01.755982v2.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002727"},{"key":"2026100808500718000_2026.10.01.755982v2.19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI90606"},{"key":"2026100808500718000_2026.10.01.755982v2.20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601987"},{"key":"2026100808500718000_2026.10.01.755982v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2026100808500718000_2026.10.01.755982v2.22","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201304143"},{"key":"2026100808500718000_2026.10.01.755982v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.06.046"},{"key":"2026100808500718000_2026.10.01.755982v2.24","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1210-1248"},{"key":"2026100808500718000_2026.10.01.755982v2.25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.099481"},{"key":"2026100808500718000_2026.10.01.755982v2.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1860-14.2014"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.10.01.755982","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:50:14Z","timestamp":1791474614000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.10.01.755982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":26,"URL":"https:\/\/doi.org\/10.64898\/2026.10.01.755982","relation":{},"subject":[],"published":{"date-parts":[[2026,10,2]]},"subtype":"preprint"}}